Identifying genetic modifiers of severity in ADPKD

描述（由申请人提供）： 常染色体显性遗传性多囊肾病（ADPKD）与孟德尔遗传病相关的表型是高度可变的。肾囊肿的病因是什么？以往的研究表明，基因（PKD 1或PKD 2）和（在较小程度上）等位基因因素影响表型，但最重要的调节因素之一是遗传背景。鉴定显著影响疾病严重程度的数量性状基因座（QTL）将有助于理解发病机制，具有预后重要性，并可能指导治疗。高密度SNP阵列的发展提供了一种方法，利用全基因组关联研究（GWAS）在大型的、临床和遗传特征良好的群体中定位这些QTL。NIDDK资助的CRISP和HALT PKD研究有一个超过1,000名ADPKD患者的联合队列，这些患者在临床和遗传上具有高度特征;超过700名患者有肾脏MR成像数据。MR计算的总肾脏体积（TKV）已被证明是疾病严重程度的良好衡量标准，在GFR下降可检测之前提供信息。此外，在UCHSC、Emory、马约、KUMC、多伦多、剑桥和牛津都可以获得充分表征的PKD 1群体，以帮助区分真正QTL与假阳性关联所需的发现、复制和验证步骤。在这里，我们提出了一个GWAS采用Illumina Human 660 w-quad基因分型珠芯片（658，000个SNP），在1600个PKD 1高加索人（目标1）。将获得约1100例患者的总肾脏体积（TKV）数据和约900例病例的信息性eGFR数据。如上所述，将使用定制阵列在1600例具有TKV和eGFR表型终点的PKD 1患者的重复人群中进一步分析与这些终点检测到的7600个最可能相关的SNP（目的2）。最终验证步骤将分析具有相同终点的1216例患者人群中的30个最有希望的基因座（目标3）。30个基因座将分别用~12个SNP（总共348个）进行测试，以细化QTL并突出可能的致病基因。为了最大限度地发挥研究的功效，我们将分析数据作为一个组合的人口和家庭为基础的关联研究。总之，该研究小组将在ADPKD中进行首次GWAS，以确定疾病严重程度的修饰因子。三阶段设计;将采用发现、复制和验证步骤来最大化鉴定QTL的机会并最小化假阳性。

DESCRIPTION (provided by applicant): The phenotype associated with the Mendelian disease autosomal dominant polycystic kidney disease (ADPKD) is highly variable. Of paramount importance clinically is the severity of the renal cystic disease. Previous studies have shown that genic (PKD1 or PKD2) and (to a less extent) allelic factors influence the phenotype, but one of the most important modulating factors is genetic background. Identifying quantitative trait loci (QTL) that significantly influence the severity of disease would help understand pathogenesis, be of prognostic importance and may guide therapeutics. The development of high-density SNP arrays provides a means to map these QTL in large, clinically and genetically well-characterized populations, employing a genome-wide association study (GWAS). The NIDDK-funded CRISP and HALT PKD studies have a combined cohort of >1,000 ADPKD patients who are highly characterized clinically and genetically; >700 have renal MR imaging data. MR calculated total kidney volume (TKV) has been shown to be a good measure of disease severity, informative before a decline in GFR is detectable. Additionally, well characterized PKD1 populations are available at UCHSC, Emory, Mayo, KUMC, Toronto, Cambridge and Oxford to aid the discovery, replication and verification steps that are required to differentiate genuine QTL from false positive associations. Here, we propose a GWAS employing the Illumina Human660w-quad Genotyping BeadChip (658,000 SNPs), in 1600 PKD1 Caucasians (Aim 1). Total kidney volumes (TKV) data will be available in ~1100 of these patients and informative eGFR data in ~900 cases. The 7600 most likely associated SNPs detected with these endpoints will be further assayed using a customized array in a replicate population of 1600 PKD1 patients with the TKV and eGFR phenotypic endpoints, as above (Aim 2). A final verification step will analyze the 30 most promising loci in a population of 1216 patients with the same endpoints (Aim 3). The 30 loci will each be tested with ~12 SNPs (total of 348) to refine the QTL and highlight possible causative genes. To maximize the power of the study we will analyze the data as a combined population and family-based association study. In summary, this consortium of groups will perform the first GWAS in ADPKD to identify modifiers of disease severity. A three-stage design; discovery, replication and verification steps are to be employed to maximize the chance to identify QTL and minimize false positives.